Methods for producing a low-substituted hydroxypropylcellulose powder

ABSTRACT

Provided are a low-substituted hydroxypropylcellulose powder having high compressibility, good flowability and excellent disintegration, and a method for producing the same. More specifically, provided is a method for producing a low-substituted hydroxypropylcellulose powder having a molar substitution number per anhydrous glucose unit of 0.05 to 1.0, which is insoluble in water and swollenable by absorbing water, comprising the steps of: adding an aqueous sodium hydroxide solution to powdered pulp in such a manner that weight ratio of sodium hydroxide with respect to anhydrous cellulose is 0.1 to 0.3 so as to produce alkali cellulose; etherifying the obtained alkali cellulose to obtain a crude product; neutralizing the sodium hydroxide contained in the obtained crude reaction product; washing the resultant; drying; and pulverizing using by compaction-grinding.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims priority to Japanese Patent ApplicationNos. 2006-215401, filed Aug. 8, 2006 and 2006-287858, filed Oct. 23,2006, the disclosures of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to low-substituted hydroxypropylcellulosethat is added for providing disintegration or compressibility at thetime of production of a preparation, in the field of medicines, foods,or the like. More specifically, the present invention relates tolow-substituted hydroxypropylcellulose that is excellent in particularin compressibility and disintegration.

2. Description of the Related Art

In solid dosage forms in the field of medicines, foods, or the like, apreparation produced only from a principal ingredient has the problemsthat the drug action may not be sufficiently exerted because sufficientdisintegration is not obtained when the drug is administered, and thatthe shape of a tablet or a granule produced therefrom may not be keptdue to its poor compressibility. In this case, the disintegration can beimproved by adding a disintegrant such as low-substitutedhydroxypropylcellulose, calcium salts of carboxymethyl cellulose,crosslinked carboxymethylcellulose sodium, crosslinkedpolyvinylpyrrolidone, or carboxymethyl starch. Furthermore, thecompressibility can be improved by adding crystalline cellulose or awater-soluble binder. Low-substituted hydroxypropylcellulose is known asa unique additive having both of the disintegration and thecompressibility.

Since low-substituted hydroxypropylcellulose is nonionic, there is anadvantage in that alteration is less caused by reaction with an ionicdrug, for example. Japanese Patent Application Examined Publication Nos.48-38858/1973 and 57-53100/1982 described that low-substitutedhydroxypropylcellulose can be used as an additive of medicines.

As described in Japanese Patent Application Examined Publication No.48-38858/1973, Japanese Patent Application Examined Publication No.57-3100/1982, Japanese Patent Application Unexamined Publication No.10-305084/1998, Japanese Patent Application Unexamined Publication No.11-322802/1999, and Japanese Patent Application Unexamined PublicationNo. 7-324101/1995, examples of a method for preparing alkali celluloseinclude a method in which sheet-shaped pulp is immersed in an aqueoussodium hydroxide solution and then squeezed. In this method,sheet-shaped pulp is immersed in an aqueous sodium hydroxide solution,and thus an excessive amount of aqueous sodium hydroxide solution isabsorbed by the pulp. Accordingly, when the pulp is squeezed, all thatis produced is alkali cellulose containing an excessive amount of wateror sodium hydroxide. Thus, the selectivity for side reactions increases,and the efficiency of etherification, which is a main reaction, is low.

As described in Japanese Patent Application Unexamined Publication No.10-305084/1998, conventional low-substituted hydroxypropylcellulose canbe obtained by reacting alkali cellulose and propylene oxide. Inetherification, cellulose is etherified as a main reaction, andpropylene glycol is produced as a side reaction due to reaction betweenpropylene oxide and water. The amount of propylene oxide used for thisetherification varies depending on the amount of aqueous sodiumhydroxide solution used as a reaction catalyst, and there is the problemthat the reaction efficiency is lowered when the amount of water orsodium hydroxide in the alkali cellulose is too large.

On the other hand, a production method in which an aqueous sodiumhydroxide solution is dropped or sprayed and thus mixed with powderedpulp is advantageous in that the amount of water of sodium hydroxide inthe alkali cellulose can be freely adjusted.

Furthermore, as described in Japanese Patent Application UnexaminedPublication No. 10-305084/1998, in a case where a crude reaction productis dissolved by loading the reaction product into hot water containingacids curing neutralization of alkali remaining in the crude reactionproduct, then obtained low-substituted hydroxypropylcellulose is in theform of fibers as in the raw material pulp, is excellent in washability,and can be easily refined, but it is poor in milling characteristics,and thus a powder having excellent flowability cannot be obtained.

Japanese Patent Application Examined Publication No. 57-53100/1982described a method for controlling fiber portions by partiallyneutralizing alkali used as a reaction catalyst in water, and partiallydissolving low-substituted hydroxypropylcellulose, after completion ofetherification. It was described that in this method, when the amount ofalkali remaining is increased, the amount of fibrous substances isreduced due to dissolution, so that an obtained milled product has highbulk density and good flowability, but the washability is lowered at thetime of refinement.

Japanese Patent Application Unexamined Publication No. 10-305084/1998described that when the water content of a washed and dehydrated productis 70 to 90% by weight, the milling characteristics are improved, andthus a low-substituted hydroxypropylcellulose powder can be obtainedthat has a degree of compression of 42% or less and a repose angle of48° or less. It was also described that milling is performed using animpact-type mill such as a hammer mill.

However, in an impact-type mill, a product is easily affected by theinfluence of a milling raw material, and the powder properties of theproduct are determined by the shape of the milling raw material. Morespecifically, when milling, with an impact-type mill, fibrous rawmaterials that are obtained by increasing the partial neutralizationamount as in Japanese Patent Application Unexamined Publication No.57-53100/1982, or by performing neutralization by loading a reactionproduct into water or hot water containing acids in an amount equivalentto sodium hydroxide that remains in the crude reaction product, withoutperforming a dissolution step, then the obtained milled product is apowder containing a large amount of fibrous particles and having lowflowability. Furthermore, this method has low throughput and lowproductivity because milling is performed by applying high energy in ashort time.

Furthermore, low-substituted hydroxypropylcellulose produced by theabove-described method has a problem in that when dissolution isperformed with a smaller partial neutralization amount in order toimprove the flowability of a powder, the amount of fiber portions isreduced and thus the compressibility is lowered. Furthermore, when theamount of fiber portions is increased by increasing the partialneutralization amount in order to improve the compressibility, there isa problem in that the flowability is lowered.

The powder obtained according to Japanese Patent Application UnexaminedPublication No. 10-305084/1998, in which the water content of a washedand dehydrated product is controlled to 70 to 90% by weight, containsfibrous particles and spherical particles in a mixed manner. Due to theinfluence of the fibrous particles, the flowability is insufficient.Thus, when a tablet is produced by direct tableting, the weightvariation of the tablet may be large. Furthermore, due to lowcompressibility of the spherical particles, the compressibility of themixed powder is insufficient.

Japanese Patent Application Unexamined Publication No. 11-322802/1999described that when fibrous particles are completely dissolved,low-substituted hydroxypropylcellulose having high flowability can beobtained. However, the compressibility of a powder obtained by thismethod is low.

Furthermore, Japanese Patent Application Examined Publication No.57-53100/1932 described that when milling is performed using a ball millinstead of impact milling, the compressibility is poor. Moreover, whenmilling is performed using a ball mill, the swelling properties, whichare important properties as a disintegrant, are low.

Japanese Patent Application Unexamined Publication No. 2001-9316described water-soluble cellulose ether in which a vertical roller millis used for powdering pulp, and thus the bulk density of the powderedpulp is increased, so that the amount of fibers that are not dissolvedwhen the cellulose ether is dissolved in water is small.

However, water-soluble cellulose ether is different from water-insolublelow-substituted hydroxypropylcellulose, in that a neutralization step,which is essential for producing low-substituted hydroxypropylcellulose,is not performed. Furthermore, in Japanese Patent Application UnexaminedPublication No. 2001-9316, there is no description on compressibilityand disintegration, which are important properties of low-substitutedhydroxypropylcellulose.

Japanese Patent Application Unexamined Publication No. 9-76233/1997described a method for producing cellulose ether using a vertical rollermill, but this method relates not to water-insoluble low-substitutedhydroxypropylcellulose but to water-soluble cellulose ether, in asimilar manner.

Japanese Patent Application Unexamined Publication No. 7-324101/1995described low-substituted hydroxypropylcellulose having a repose angleof 45° or less and a swollen volume increase ratio of 100% or more, butthe compressibility of this low-substituted hydroxypropylcellulose islow.

SUMMARY OF THE INVENTION

The present invention was completed for solving the problems of theabove-descried conventional techniques. It is an object thereof toprovide a low-substituted hydroxypropylcellulose powder having highcompressibility, good lowability and excellent disintegration, and amethod for producing the same.

The inventors had conducted an in-depth study in order to achieve theabove-described object, and found that a low-substitutedhydroxypropylcellulose powder having high compressibility, goodflowability and excellent disintegration can be obtained by the methodfor producing low-substituted hydroxypropylcellulose wherein an aqueoussodium hydroxide solution is added to and mixed with powdered pulp so asto produce alkali cellulose in which the weight ratio of sodiumhydroxide with respect to anhydrous cellulose is 0.1 to 0.3; the alkalicellulose is etherified; subsequently, the sodium hydroxide isneutralized after performing or without performing a dissolution step;the resultant is washed and dried; and then the dried product iscompaction-ground in a pulverization step.

More specifically, the present invention provides a method for producinga low-substituted hydroxypropylcellulose powder having a molarsubstitution number per anhydrous glucose unit (in other words, thenumber of moles substituted with hydroxypropoxyl groups per anhydrousglucose unit) of 0.05 to 1.0, which is insoluble in water andswollenable by absorbing water, comprising the steps of: (1) adding anaqueous sodium hydroxide solution to powdered pulp in such a manner thatweight ratio of sodium hydroxide with respect to anhydrous cellulose is0.1 to 0.3 so as to obtain alkali cellulose; (2) etherifying theobtained alkali cellulose so as to obtain a crude reaction product; (3)neutralizing the sodium hydroxide contained in the obtained crudereaction product; (4) washing and dehydrating the resultant; (5) drying;and (6) pulverizing by using compaction-grinding. Furthermore, thepresent invention provides a method for producing a low-substitutedhydroxypropylcellulose powder having a molar substitution number peranhydrous glucose unit of 0.05 to 1.0, which is insoluble in water andswollenable by absorbing water, comprising the steps of: (1) adding anaqueous sodium hydroxide solution to powdered pulp in such a manner thatthe weight ratio of sodium hydroxide with respect to anhydrous celluloseis 0.1 to 0.3 so as to obtain alkali cellulose; (2) etherifying theobtained alkali cellulose so as to obtain a crude reaction product; (3)neutralizing the sodium hydroxide contained in the obtained crudereaction product without performing a step of dissolving part or wholeof the crude reaction product; (4) washing and dehydrating theresultant; (5) drying; and (6) pulverizing using by compaction-grinding.

It is preferable that in said step of washing and dehydrating, saidresultant is washed and dehydrated such that a water content is notgreater than 65% by weight. Furthermore, the present invention providesa low-substituted hydroxypropylcellulose powder having an averageparticle size of 10 to 100 μm and a specific surface area measured byBET method of at least 1.0 m²/g. It is preferable that thelow-substituted hydroxypropylcellulose powder has an elastic recoveryratio of not greater than 7% when compressed at a compression force of50 MPa. It is preferable that the low-substituted hydroxypropylcellulosepowder has a swollen volume increase ratio of at least 300% and aswollen volume increase rate of at least 100%/min when absorbing water.It is preferable that the low-substituted hydroxypropylcellulose powderhas a repose angle of not greater than 42°.

Moreover, the present invention provides a solid dosage form using thislow-substituted hydroxypropylcellulose powder.

The low-substituted hydroxypropylcellulose powder of the presentinvention has high flowability, excellent compressibility and excellentswelling properties, regardless of the fibrous form derived from rawmaterial pulp.

The low-substituted hydroxypropylcellulose powder of the presentinvention is advantageous also in that due to its excellentcompressibility and excellent disintegration, the amount of this powderadded to a tablet can be reduced, and thus the size of the tablet can bemade smaller.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an electron micrograph of a powder obtained in Example 1.

FIG. 2 shows an electron micrograph of a powder obtained in ComparativeExample 4.

FIG. 3 shows an electron micrograph of a powder obtained in ComparativeExample 5.

FIG. 4 shows an electron micrograph of a powder obtained in ComparativeExample 6.

FIG. 5 shows the time-series swollen volume increase ratio, of powdersobtained in Examples 1 to 3 and Comparative Examples 1 and 3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the method of the present invention is described. First,any milling method may be applied for obtaining powdered pulp that isused as a raw material. The average particle size thereof is preferably60 to 300 μm. It may be inefficient from an industrial viewpoint toprepare powdered pulp having an average particle size of less than 60μm. If the average particle size is more than 300 μm, then theuniformity with an aqueous sodium hydroxide solution may be poor.

The step of producing alkali cellulose is preferably performed bydropping or spraying the aqueous sodium hydroxide solution to thepowdered pulp and mixing the resultant. At that time, the sodiumhydroxide acts as a catalyst in the etherification. The alkali cellulosemay be produced preferably by using either a method in which mixing isperformed in an internally-agitating type reaction device, and thenetherification is successively performed, or a method in which alkalicellulose prepared in another mixing device is charged into a reactiondevice, and etherification is performed.

Furthermore, it was found that the amount of the sodium hydroxide in thealkali cellulose affects not only the reaction efficiency but also theswelling properties and the compressibility of final products. Theoptimum amount of the sodium hydroxide in the alkali cellulose may be0.1 to 0.3 in the weight ratio of the sodium hydroxide with respect toanhydrous cellulose (referring to the balance obtained by removing waterfrom the pulp). If the amount: is less than 0.1, then the swellingproperties, in particular, the volume increase ratio when the product isswollen by absorbing water may be lowered, the disintegration may belowered, and the compressibility also may be lowered. Furthermore, ifthe amount is more than 0.3, then the swollen volume increase ratio andthe swollen volume increase rate when absorbing water (described later)may be lowered, and the compressibility also may be lowered.

The sodium hydroxide is preferably added as an aqueous 20 to 40% byweight solution.

The following etherification step may be performed by charging thealkali cellulose into a reaction device, performing nitrogen purge, andthen charging propylene oxide into the reaction device as an etherifyingagent, thereby causing a reaction. The charge of the propylene oxidecharged is preferably approximately 0.1 to 1.0 mole with respect to 1mole of anhydrous glucose units. The reaction temperature isapproximately 40 to 80° C., and the reaction time is approximately 1 to5 hours.

It should be noted that after the etherification step, a dissolutionstep may be performed, if necessary. The dissolution step is performedby dissolving part or whole of the crude reaction product after theetherification in water or hot water. The amount of water or hot waterused varies depending on the amount of the crude reaction product to bedissolved, but the amount of water for dissolving whole of the crudereaction product is usually 0.5 to 10 in the weight ratio with respectto the low-substituted hydroxypropylcellulose in the crude reactionproduct.

In order to further improve the load in the wash and dehydration stepdescribed later, and the compressibility of low-substituted celluloseether, it is preferable not to perform the dissolution step.

In the following neutralization step, since the sodium hydroxide used asthe catalyst remains in the reaction product, neutralization ispreferably performed by loading the crude reaction product into water orhot water containing acids in an amount equivalent to the sodiumhydroxide. Alternatively, neutralization may be performed by addingwater or hot water containing the equivalent amount of acids to thereaction product.

Examples of the acids that are used herein include mineral acids such ashydrochloric acid, sulfuric acid, and nitric acid, and organic acidssuch as fcmic acid and acetic acid.

In the following wash and dehydration step, while washing the obtainedneutralized product preferably using water or hot water, dehydration isperformed by a method preferably selected from centrifugation, suctionfiltration, and pressure filtration, for example. The low-substitutedhydroxypropylcellulose in an obtained dehydrated product cake is in theform of fibers as in the raw material pulp. The dehydrated productobtained after performing the dissolution step has a dehydration ratioof approximately 70 to 90% by weight, although this ratio depends on thenumber of moles substituted. The dehydration ratio of the dehydratedproduct obtained without performing the dissolution step is usually 65%by weight or less, so that the load in the following drying step can bereduced, and the productivity is improved. Furthermore, it isadvantageous in that the steps can be simplified because the dissolutionstep is not included.

Furthermore, in view of the compressibility of the product, when millinga fibrous substance, the obtained product has higher specific surfacearea and thus higher compressibility.

The drying step of drying the obtained dehydrated product is preferablyperformed using a drier such as a fluidized bed drier or a drum drier at60 to 120° C.

The milling step is performed by compaction-grinding the dried productobtained by the above-described method.

For this compaction-grinding, mills such as a roller mill, a ball mill,a bead mill, or a millstone mill can be used. In a roller mill, with acentrifugal force or gravity load accompanying its rotational movement,rollers or balls roll over while compressing/shearing a milling targeton a mill wall. Examples thereof include an IS mill manufactured byIshikawajima-Harima Heavy Industries Co., Ltd., a VX mill manufacturedby Kurimoto, Ltd., and an MS roller mill manufactured by MASUNOSEISAKUSHO LTD. A ball mill uses, as a milling medium, steel balls,magnetic balls, cobbled stones, or the like. Examples thereof include aball mill manufactured by KURIMOTO TEKKO KK, a tube mill manufactured byOtsuka Iron Works, and a planetary ball mill manufactured by FRITSCH. Abead mill is similar to the ball mill, but is different therefrom inthat the diameter of balls used is smaller and in that acceleration ofthe balls can be further increased by rotating the internal portion ofthe device at high speed. Examples thereof include a bead millmanufactured by Ashizawa. A millstone mill can grind a powder byrotating a millstone at narrow clearance at high speed. Examples thereofinclude Serendipiter manufactured by MASUKO SANGYO CO., LTD.

The roller mill is particularly preferable because it reduces foreignmetal substances mixed in, requires small installation area, andprovides high productivity.

It has been considered that the compressibility of low-substitutedhydroxypropylcellulose produced by conventional impact milling isexerted by intertwining of fibrous substances. When fibrous particlesare increased based on this idea for improving the compressibility, theflowability is lowered. However, a low-substitutedhydroxypropylcellulose powder of the present invention exhibitssurprisingly high compressibility, although the fibrous form has beenlost due to the compaction-grinding.

As described in Japanese Patent Application Examined Publication No.57-53100/1982 and Japanese Patent Application Unexamined Publication No.10-305084/1998, the powder properties of the product have beenconventionally adjusted by controlling the amount of fibrous particles,by partially neutralizing sodium hydroxide used as a reaction catalystin water, and partially dissolving low-substitutedhydroxypropylcellulose, after completion of etherification. Furthermore,in Japanese Patent Application Unexamined Publication No.11-322802/1999, a powder having high flowability is prepared bycompletely dissolving low-substituted hydroxypropylcellulose. In all ofthese methods, milling is performed using an impact-type mill such as animpact mill that uses an impact force.

In an impact-type mill, a product is easily affected by the influence ofa milling raw material, and the powder properties of the product aredetermined by the shape of the milling raw material. More specifically,in a case where fibrous raw materials are used that are obtained, as inJapanese Patent Application Examined Publication No. 57-53100/1982 andJapanese Patent Application Unexamined Publication No. 10-305084/1998,by increasing the partial neutralization amount, or by performingneutralization by loading a reaction product into water or hot watercontaining acids in an amount equivalent to sodium hydroxide thatremains in the crude reaction product, without performing a dissolutionstep that is an Embodiment of the present invention, then the obtainedpulverized product is a powder containing a large amount of fibrousparticles and having low flowability.

According to the present invention, when fibrous particles serving as amilling raw material may be repeatedly compaction-ground, the fibrousand hollow tubular form derived from the raw material pulp is lost, andthus primary particles can be made smaller, so that the specific surfacearea is increased. Also, since the fibrous form derived from the rawmaterial pulp is lost, a powder having uniform particle shape can beobtained.

Next, preferably, the pulverized product may be sieved following theusual method, and thus the targeted low-substitutedhydroxypropylcellulose powder can be obtained. The opening of a sieveherein may be approximately 75 to 180 μm.

The average particle size of the low-substituted hydroxypropylcellulosepowder of the present invention is preferably approximately 10 to 100μm, and more preferably approximately 20 to 60 μm. If the averageparticle size is less than 10 μm, then aggregability increases becausethe hydroxypropylcellulose is in the form of fine powder, and thus theflowability of the powder may be lowered. If the average particle sizeis more than 100 μm, then uniformity with the drug is lowered, and thusthe product may be non-uniform.

The specific surface area of the low-substituted hydroxypropylcellulosepowder of the present invention is preferably 1.0 m²/g or more. If thespecific surface area is less than 1.0 m²/g, then high compressibilitymay not be obtained.

It is known that generally, higher specific surface area of a powderprovides higher compressibility of the powder. The specific surface areaanalysis is a method for obtaining the specific surface area of a samplebased on the amount of molecules adsorbed to the surface of particles ofthe powder at the temperature of liquid nitrogen, the molecules havingadsorption occupying area that has been known. For the specific surfacearea analysis, the BET method can be used that is based on physicaladsorption of inert gas at low temperature and low humidity. In themeasurement, for example, MICROMERITICS GEMINI 2375 (manufactured bySHIMADZU CORPORATION) can be used.

Generally, specific surface area can be increased by reducing averageparticle size. However, as described above, if average particle size istoo small, then the aggregability of a powder increases, and theflowability of the powder may be lowered. In the present invention,using compaction-grinding, a powder is provided that has high specificsurface area although its average particle size is sufficient forsecuring the flowability of the powder.

Elastic recovery ratio refers to an indicator of the compressibility ofa powder. The elastic recovery ratio can be calculated from thefollowing equation, based on the thickness of a tablet obtained bycompression a powder in a tablet weight of 480 mg and at a compressionforce of 50 MPa, using a flat shape with a flat contact face for atablet diameter of 11.3 mm.

Elastic  recovery  ratio = {(tablet  thickness  after  30  seconds − minimum  tablet  thickness)/(minimum  tablet  thickness)/(minimum  tablet  thickness)} × 100

Herein, “minimum tablet thickness” refers to the lowest point obtainedwhen the powder is compressed by an upper punch of a flat shape unitwith a fixed lower punch, that is, the thickness obtained when thetablet is compressed to the extent possible. “Tablet thickness after 30seconds” refers to the tablet thickness at 30 seconds after the upperpunch is removed upward.

The elastic recovery ratio of the low-substituted hydroxypropylcellulosepowder of the present invention is preferably 7% or less, and it wasfound that this low-substituted hydroxypropylcellulose powder is aplastically deformable member similar to crystalline cellulose commonlyused as a binder, and is a powder that forms a dense molded product in acompressed state. A powder produced by the method described in PatentJapanese Patent Application Examined Publication No. 57-53100/1982 andJapanese Patent Application Unexamined Publication No. 2001-9316 hashigh elastic recovery ratio and substantially is an elasticallydeformable member.

The swelling properties of the low-substituted hydroxypropylcellulosepowder of the present invention can be measured, for example, in thefollowing manner: the low-substituted hydroxypropylcellulose powder ismolded at a compression force of 1 t into a tablet having a flat facewith a diameter of 15 mm; the tablet is swollen by dropping waterthereonto; and the swelling properties are evaluated as the swollenvolume increase ratio and the swollen volume increase rate at that time.When alkali cellulose is used in which the weight ratio of sodiumhydroxide with respect to anhydrous cellulose is 0.1 to 0.3, the swollenvolume increase ratio is preferably 300% or more, and the swollen volumeincrease rate is preferably 100%/min or more.

The swollen volume increase ratio can be obtained in the followingmanner: the powder is molded at a compression force of 1 t into a tablethaving a flat face with a diameter of 15 mm; a punch with a pipe isattached instead of the upper punch; the tablet is caused to absorbwater for 10 minutes by dropping water through this pipe onto the tabletcontained in a mortar; and the swollen volume increase ratio is obtainedat that time. The water is dropped at a rate of 1 ml/min for 10 minutes.The increase in the volume can be calculated from the followingequation, based on a change in the thickness of the tablet.

Swollen  volume  increase  ratio = (difference  in  tablet  thickness  between  before  and  after  adding  water/tablet  thickness  before  adding  water) × 100

It should be noted that in the equation above, “difference in tabletthickness between before and after adding water” refers to a valueobtained by subtracting the tablet thickness before adding water fromthe tablet thickness after adding water for 10 minutes.

The swollen volume increase ratio of the low-substitutedhydroxypropylcellulose powder of the present invention is preferably300% or more in view of swelling properties, which are importantproperties as the disintegrant. If the swollen volume increase ratio isless than 300%, then the disintegration time of a preparation producedfrom the powder may be longer.

The swollen volume increase rate refers to an initial swelling ratio at30 seconds after starting the addition of water, when the swollen volumeincrease ratio is measured under the same condition as theabove-described method, and can be calculated from the followingequation.Swollen volume increase rate=(difference in tablet thickness before andafter initially adding water/tablet thickness before addingwater)×100/0.5

In the equation above, “difference in tablet thickness before and afterinitially adding water” refers to a value obtained by subtracting thetablet thickness before adding water from the tablet thickness at 30seconds after starting the addition of water.

The swollen volume increase rate of the low-substitutedhydroxypropylcellulose powder of the present invention is preferably100%/min or more in view of swelling properties, which are importantproperties as the disintegrant. If the swollen volume increase rate isless than 100%/min, then the disintegration time of a preparationproduced from the powder may be longer.

The low-substituted hydroxypropylcellulose powder of the presentinvention is a powder having high flowability and preferably having arepose angle of 42° or less, the repose angle being one type ofindicators of the flowability of a powder. The repose angle refers to anangle formed by a horizontal plane and a generatrix of a corn that is adeposition formed by dropping the sample onto the plane. For example,using a powder tester PT-D (manufactured by Hosokawa MicronCorporation), the repose angle can be calculated by allowing the sampleto flow from a height of 75 mm onto a disc-shaped metal stage having adiameter of 80 mm, until a constant angle is obtained, and thenmeasuring the angle formed by the deposited powder and the stage. Thesmaller this angle is, the better the flowability of the powder is.

Furthermore, as an indicator of compressibility, the hardness of atablet can be evaluated when the tablet is obtained by compression asample powder in a tablet weight of 480 mg and at a compression force of150 MPa, using a flat shape for a tablet diameter of 11.3 mm. Thehardiness of a tablet obtained using the low-substitutedhydroxypropylcellulose powder of the present invention is preferably 35kgf or more, and particularly preferably 40 kgf or more. Tablet hardnesscan be evaluated, for example, by performing tableting under theabove-described conditions using a tableting tester (manufactured bySANKYO PIO-TECH. CO., Ltd.). It should be noted that tableting ispreferably performed at a constant water content of a sample powder,because the obtained tablet hardness varies depending on the watercontent of the sample powder. Tableting is preferably performed afteradjusting the water content of the sample powder, for example, to 2 to4% by weight.

Furthermore, evaluation can be performed also based on the bulk densityof the low-substituted hydroxypropylcellulose powder. For example, bulkdensity can be obtained using a powder tester (manufactured by HosokawaMicron Corporation), by measuring the weight when loosely filling (thatis, without tapping) a vessel with a volume of 100 ml. The bulk densityof the low-substituted hydroxypropylcellulose powder of the presentinvention is preferably 0.3 to 0.5 g/ml, and particularly preferably0.35 to 0.45 g/ml. If the bulk density is less than 0.3 g/ml, then theflowability of the powder may be lowered, which is not be preferable forhandling. If the bulk density is more than 0.5 g/ml, then thecompressibility may be lowered.

The low-substituted hydroxypropylcellulose powder of the presentinvention can be used as a binder or a disintegrant of a solid dosageform such as a tablet or a granule. A tablet can be obtained using anyproduction methods such as a dry direct tableting method, a wetagitation-granulation tableting method, a fluidized bed granulationtableting method, and a dry granulation tableting method.

Herein, the dry direct tableting method refers to a method in which alow-substituted hydroxypropylcellulose powder, a drug, and otheringredients such as a vehicle and a lubricant are dry-mixed and thentableting is performed. In this method, the production steps can besimplified because a granulating step is not included, and theproductivity is high. The wet agitation-granulation tableting methodrefers to a method in which a low-substituted hydroxypropylcellulosepowder, a drug, and other ingredients such as a vehicle are granulatedwith water or a water-soluble binder solution using a high-speedagitation granulating device, a powder obtained by drying the resultantand a lubricant are mixed, and then tableting is performed. This methodprovides high uniformity of the drug content. The fluidized bedgranulation tableting method refers to a method in which alow-substituted hydroxypropylcellulose powder, a drug, and otheringredients such as a vehicle are granulated with water or awater-soluble binder solution using a fluidized bed granulating device,a powder obtained by drying the resultant and a lubricant are mixed, andthen tableting is performed. This method provides high uniformity of thedrug content, as in the wet agitation-granulation tableting method. Thedry granulation tableting method refers to a method in which alow-substituted hydroxypropylcellulose powder, a drug, and otheringredients such as a vehicle are granulated by compression and thentableting is performed. This method is effective for a drug that issensitive to water or a solvent. Furthermore, this method can be appliedalso to oral rapidly disintegrating tablets that are rapidlydisintegrated in the oral cavity without water or with a small amount ofwater, which have been actively developed recently. This method providesa dosage form that is effective for elderly and children having poorswallowing ability.

Moreover, the low-substituted hydroxypropylcellulose of the presentinvention can be used also as a binder or a disintegrant of a granule. Agranule can be obtained using any production methods such as the wetagitation granulation, the fluidized bed granulation, and the drygranulation.

A cylindrical granule produced by extrusion granulation and a granulatedmatter after extrusion granulation can be spheroidized using amarumerizer. Furthermore, layering also can be performed in which abinder solution is sprayed in a state where a mixed powder of alow-substituted hydroxypropylcellulose powder, a drug powder, and otheringredients such as a vehicle is scattered over a spherical core made ofsugars or the like.

There is no particular limitation on the drug used for producing apreparation from the low-substituted hydroxypropylcellulose powder ofthe present invention, and examples thereof include drugs for thecentral nervous system, drugs for the circulatory system, drugs for therespiratory system, drugs for the digestive system, antibiotics,chemotherapeutics, drugs for the metabolic system, and vitamin-baseddrugs.

Examples of the drugs for the central nervous system include diazepam,idevenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam,diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenyloin,acetaminophen, ethenzamide, and ketoprofen.

Examples of the drugs for the circulatory system include molsidomine,vinpocetine, propranolol, methyldopa, dipyridamole, furosemide,triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol,captopril, and isosorbide nitrate.

Examples of the drugs for the respiratory system include amlexanox,dextromethorphan, theophylline, pseudoephedrine, salbutamol, andguaifenesin.

Examples of the drugs for the digestive system include:benzimidazole-based drugs having an antiulcer action, such as2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl}benzimidazole, and5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole; cimetidine; ranitidine; pancreatin; bisacodyl; and5-aminosalicylic acid.

Examples of the antibiotics and the chemotherapeutics includecephalexin, cefaclor, cephradine, amoxicillin, pivampicillin,bacampicillin, dicloxacillin, erythromycin, erythromycin stearate,lincomycin, doxycycline, and trimethoprim/sulfamethoxazole.

Examples of the drugs for the metabolic system include serrapeptase,lysozyme chloride, adenosine triphosphate, glibenclamide, and potassiumchloride.

Examples of the vitamin-based drugs include vitamin B1, vitamin B2,vitamin B6, and vitamin C.

EXAMPLES

Hereinafter, the present invention is described in detail by way ofexamples, but the present invention is not limited to these examples.

Example 1

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 303 g of 26% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.105. Next, nitrogen purge wasperformed, 123 g of propylene oxide (0.164 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 1232 g ofhydroxypropylcellulose crude reaction product was obtained in which themolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.28. The etherification efficiency was 61.4%.

Next, 236 g of 50% by weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 58.2% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated by the following method, in terms of averageparticle size, specific surface area, bulk density, repose angle,elastic recovery ratio, compressibility, swollen volume increase ratio,and swollen volume increase rate. Table 1 shows the results. FIG. 1shows an electron micrograph of the obtained powder. FIG. 1 shows thatthe powder had lost a fibrous form with a smooth surface derived fromthe raw material pulp by compaction-grinding, had a constant shape, andcontained voids.

The average particle size was measured using a HELOS&RODOS (manufacturedby Sympatec) for measuring particle size distribution with laserdiffractometry.

The specific surface area was measured using a MICROMERITICS GEMINI 2375(manufactured by SHIMADZU CORPORATION).

The bulk density was obtained using a powder tester (manufactured byHosokawa Micron Corporation), by uniformly and loosely (that is, withouttapping) filling the sample from above (23 cm), through a sieve with 24mesh according to JIS, into a 100 cc cylindrical vessel (made ofstainless steel) with a diameter of 5.03 cm and a height of 5.03 cm, andthen measuring the weight after leveling at the upper surface.

The repose angle was obtained using a powder tester (manufactured byHosokawa Micron Corporation), by allowing the sample to flow from aheight of 75 mm onto a disc-shaped stage with a size of 80 mm, and thenmeasuring the angle formed by the deposited powder and the stage.

The elastic recovery ratio was calculated from the following equation,based on the thickness of a tablet obtained by compression the samplepowder in a tablet weight of 480 mg and at a compression force of 50MPa, using a tableting tester (manufactured by SANKYO PIO-TECH. CO.,Ltd.) with a flat punch for a tablet diameter of 11.3 mm.

Elastic  recovery  ratio = {(tablet  thickness  after  30  seconds − minimum  tablet  thickness)/(minimum  tablet  thickness)} × 100

The compressibility was obtained by measuring the hardness of a tabletobtained by compression the powder in a tablet weight of 480 mg and at acompression force of 150 MPa, using a tableting tester (manufactured bySANKYO PIO-TECH. CO., Ltd.) with a flat shape for a tablet diameter of11.3 mm.

The swollen volume increase ratio was obtained by molding the powder ata compression force of 1 t into a tablet having a flat face with adiameter of 15 mm, dropping water thereonto, and then measuring thevolume increase ratio after 10 minutes at which the tablet had beenswollen by absorbing the water.

The swollen volume increase rate was calculated, by molding the powderat a compression force of 1 t into a tablet having a flat face with adiameter of 15 mm, dropping water thereonto, obtaining the swollenvolume increase ratio based on a change in the volume after 30 secondsat which the tablet had been swollen, and then performing thecalculation based on this ratio.

Next, using the obtained powder, an ascorbic acid tablet was produced bydirect tableting under the following conditions.

-   -   Tablet composition:        -   ascorbic acid granulated powder VC-97 (manufactured by BASF            Takeda Vitamins Ltd.): 90 parts by weight low-substituted            hydroxypropylcellulose;            -   parts by weight        -   magnesium stearate: 0.5 parts by weight    -   Tableting machine: rotary tableting machine (manufactured by        Kikusui Seisakusho Ltd.)    -   Tablet size: diameter 3 mm, radius of curved face 6.5 mm    -   Tablet weight: 200 mg    -   Tableting pressure: main-pressure 0.5 t,        -   pre-pressure 0.2 t    -   Tableting speed: 40 rpm

The tablet hardness, the disintegration time (test fluid: water) inDisintegration Test according to Japanese Pharmacopoeia, and the tabletweight variation, of the obtained tablet were measured. Table 1 showsthe results.

Example 2

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 504 g of 26% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.175. Next, nitrogen purge wasperformed, 143 g of propylene oxide (0.190 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 1453 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.29. The etherification efficiency was 53.6%.

Next, 394 g of 50% by weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 60.5% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, specific surface area, bulk density, repose angle, elasticrecovery ratio, compressibility, swollen volume increase ratio, andswollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Example 3

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 808 g of 26% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.280. Next, nitrogen purge wasperformed, 173 g of propylene oxide (0.230 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 1787 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.30. The etherification efficiency was 46.4%.

Next, 629 g of 50% by weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 62.2% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, bulk density, repose angle, elastic recovery ratio,compressibility, swollen volume increase ratio, and swollen volumeincrease rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Example 4

First, 8.6 kg of powdered pulp (8 kg in an anhydrous state) was chargedinto a 130 L internally-agitating type reaction device, 3.5 kg of 35% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.151. Next, nitrogen purge wasperformed, 1.6 kg of propylene oxide (0.2 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 13.7 kg ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.35.

Next, 11.8 kg of 50% by weight acetic acid was added and mixed in theinternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C., using a batch-type suction filtration machine. The water content ofthe dehydrated product was 59.5% by weight. The dehydrated product wasdried at an air intake temperature of 80° C. in a fluidized bed drieruntil the discharge air temperature was 60° C. The etherificationefficiency was 57.6%.

The dried product was pulverized and dehydrated, using a roller millIS-250 manufactured by IHI, at an applied pressure of 3 MPa, a tablerotational speed of 120 rpm, a classification rotational speed of 300rpm, a gas volume of 11 Nm³/min, and a supply time of 5 kg/hr. Thepulverized product was sieved through a sieve with an opening of 75 μm,and thus the targeted low-substituted hydroxypropylcellulose powder wasobtained.

This powder was evaluated as in Example 1, in terms of average particlesize, specific surface area, bulk density, repose angle, elasticrecovery ratio, compressibility, swollen volume increase ratio, andswollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Example 5

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 303 g of 26% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.105. Next, nitrogen purge wasperformed, 81.8 g of propylene oxide (0.109 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1 hour, and thus 1190.8 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.20. The etherification efficiency was 65.0%.

Next, 2250 g of warm water at 50° C. and 59 g of glacial acetic acidwere put into a 10 L batch-type kneader, and the entire 1190.8 g of thecrude reaction product was loaded thereinto and dissolved. It took 20minutes for the crude reaction product to be completely dissolved. Then,118 g of 50% by weight acetic acid was added at a rate of 20 g/min,thereby performing neutralization. The neutralized product was washed inhot water at 90° C. and dehydrated, using a batch-type centrifuge at arotational speed of 3000 rpm. The water content of the dehydratedproduct was 62.2% by weight. The dehydrated product was dried at 80° C.for one whole day and night in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 75 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, bulk density, repose angle, elastic recovery ratio,compressibility, swollen volume increase ratio, and swollen volumeincrease rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Comparative Example 1

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 300 g of 13% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.052. Next, nitrogen purge wasperformed, 146 g of propylene oxide (0.195 parts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 1252 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.28. The etherification efficiency was 50.9%.

Next, 117 g of 50% weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 50.1% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, specific surface area, bulk density, repose angle, elasticrecovery ratio, compressibility, swollen volume increase ratio, andswollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Comparative Example 2

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 761 g of 35% byweight sodium hydroxide was charged into the reaction device, thenmixing was performed at 45° C. for 30 minutes, and thus alkali cellulosewas obtained in which the weight ratio of sodium hydroxide with respectto anhydrous cellulose was 0.355. Next, nitrogen purge was performed,161 g of propylene oxide (0.214 parts by weight with respect tocellulose) was added to the resultant, then the mixture was reacted at ajacket temperature of 60° C. for 1.5 hours, and thus 1728 g ofhydroxypropylcellulose crude reaction product was obtained in which themolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.28. The etherification efficiency was 43.5%.

Next, 800 g of 50% by weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 65.2% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, specific surface area, bulk density, repose angle, elasticrecovery ratio, compressibility, swollen volume increase ratio, andswollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Comparative Example 3

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 844 g of 43% byweight sodium hydroxide solution was charged into the reaction device,then mixing was performed at 45° C. for 30 minutes, and thus alkalicellulose was obtained in which the weight ratio of sodium hydroxidewith respect to anhydrous cellulose was 0.484. Next, nitrogen purge wasperformed, 165 g of propylene oxide (0.220 pacts by weight with respectto cellulose) was added to the resultant, then the mixture was reactedat a jacket temperature of 60° C. for 1.5 hours, and thus 1815 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.27. The etherification efficiency was 42.3%.

Next, 1088 g of 50% by weight acetic acid was added and mixed in the 10L internally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 66.8% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through a sieve with an opening of 180 μm, and thusthe targeted low-substituted hydroxypropylcellulose powder was obtained.This powder was evaluated as in Example 1, in terms of average particlesize, specific surface area, bulk density, repose angle, elasticrecovery ratio, compressibility, swollen volume increase ratio, andswollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results.

Comparative Example 4

Sheet-shaped pulp was immersed in a 43 sodium hydroxide solution andthen squeezed, and thus alkali cellulose was obtained in which 22.2% byweight sodium hydroxide was contained and the weight ratio of sodiumhydroxide with respect to anhydrous cellulose was 0.484. The obtainedalkali cellulose was cut into chips with a size of approximately 1 cmsquares, and the alkali cellulose in an amount of 350 g expressed interms of cellulose was charged into a reaction device with a volume of 5L. Then, nitrogen purge was performed. Next, 79 g of propylene oxide(0.226 parts by weight with respect to cellulose) was added to theresultant, then the mixture was reacted at a jacket temperature of 45°C. for 2 hours and 65° C. for 30 minutes, and thus 857 g ofhydroxypropylcellulose crude reaction product was obtained in which amolar substitution number of hydroxypropoxyl groups per anhydrousglucose unit was 0.27. The etherification efficiency was 42.0%.

Next, as in Japanese Patent Application Examined Publication No.57-53100/1982 and Japanese Patent Application Unexamined Publication No.10-305084/1998, a part of the crude reaction product was dissolved inhot water and then neutralized (partial neutralization), the obtaineddried product was pulverized by impact milling, and thus a sample wasobtained.

Next, 1750 g of water at 50° C. and 52 g of glacial acetic acid were putinto a 5 L batch-type kneader, and the entire 857 g of the crudereaction product was loaded thereinto and dissolved. It took 30 minutesfor the crude reaction product to be completely dissolved. Then, 633 gof 33% acetic acid was added at a rate of 20 g/min, thereby performingneutralization and precipitation.

The neutralized product was washed in hot water at 90° C., using abatch-type centrifuge at a rotational speed of 3000 rpm. The watercontent of the dehydrated product was 75.4% by weight. The dehydratedproduct was dried at 80° C. for one whole day and night in a fan oven.

The obtained dried product was pulverized using a high-rotationimpact-type mill Victory Mill having a screen with an opening of 0.3 mm.The pulverized product was sieved through a sieve with an opening of 75μm, and thus the targeted low-substituted hydroxypropylcellulose powderwas obtained. This powder was evaluated as in Example 1, in terms ofaverage particle size, specific surface area, bulk density, reposeangle, elastic recovery ratio, compressibility, swollen volume increaseratio, and swollen volume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results. FIG. 2 shows an electron micrograph of the obtainedpowder. FIG. 2 shows that the powder contained fibrous substances with asmooth surface derived from the raw material pulp, and dense sphericalparticles generated in the dissolution step, in a mixed manner.

Comparative Example 5

After the complete dissolution described in Japanese Patent ApplicationUnexamined Publication No. 11-322802/1999, neutralization was performed,the obtained dried product was pulverized by impact milling, and thus asample was obtained.

Next, 2450 g of water at 50° C. was put into a 5 L batch-type kneader,and the entire 857 g of the crude reaction product reacted as in Example4 was loaded thereinto and dissolved (completely dissolved). It took onehour for the crude reaction product to be completely dissolved. Then,793 g of 33% acetic acid was added at a rate of 20 g/min, therebyperforming neutralization and precipitation.

The neutralized product was washed in hot water at 90° C. anddehydrated, using a batch-type centrifuge at a rotational speed of 3000rpm. The water content of the dehydrated product was 80.1% by weight.The dehydrated product was dried at 80° C. for one whole day and nightin a fan oven.

The obtained dried product was pulverized using a high-rotationimpact-type mill Victory Mill having a screen with an opening of 0.3 mm.The pulverized product was sieved through a sieve with an opening of 75μm, and thus the targeted low-substituted hydroxypropylcellulose powderwas obtained. This powder was evaluated as in Example 1, in terms ofaverage particle size, bulk density, repose angle, elastic recoveryratio, compressibility, swollen volume increase ratio, and swollenvolume increase rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results. FIG. 3 shows an (electron micrograph of theobtained powder. FIG. 3 shows that the powder was constituted by asmaller amount of fibrous particles generated in the dissolution step,and dense spherical particles.

Comparative Example 6

A low-substituted hydroxypropylcellulose powder was obtained as inExample 2, except that a high-rotation impact-type mill Victory Millhaving a screen with an opening of 0.3 mm was used. This powder wasevaluated as in Example 1, in terms of average particle size, specificsurface area, bulk density, repose angle, elastic recovery ratio,compressibility, swollen volume increase ratio, and swollen volumeincrease rate. Table 1 shows the results.

Furthermore, an ascorbic acid tablet was produced by direct tableting asin Example 1. The tablet hardness, the disintegration time (test fluid:water) in Disintegration Test according to Japanese Pharmacopoeia, andthe tablet weight variation, of the obtained tablet were measured. Table1 shows the results. FIG. 4 shows an electron micrograph of the obtainedpowder. FIG. 4 shows that the powder was in the form of fibers with asmooth surface derived from the raw material pulp.

FIG. 5 shows the results obtained by observing the influence on theswelling properties, given by the weight ratio of the sodium hydroxidewith respect to the anhydrous cellulose in the alkali cellulose. In FIG.5, the horizontal axis indicates the measurement time after starting theaddition of water, and the vertical axis indicates the swollen volumeincrease ratio.

It is shown that in the examples, both of the swollen volume increaseratio and the swollen volume increase rate are larger than those in thecomparative examples.

TABLE 1 production conditions substitution water weight degree ofcontent of shape ratio hydroxypropoxyl esterification dehydrated of ofgroup efficiency product pulverization pulp NaOH* (mol) (%) (%) methodExample 1 powder 0.105 0.28 61.4 58.2 compaction-grind Example 2 powder0.175 0.29 53.6 60.5 compaction-grind Example 3 powder 0.280 0.30 46.462.2 compaction-grind Example 4 powder 0.151 0.35 57.6 59.5compaction-grind Example 5 powder 0.105 0.20 65.0 62.2 compaction-grindComp. Ex. 1 powder 0.052 0.28 50.9 50.1 compaction-grind Comp. Ex. 2powder 0.355 0.28 43.5 65.2 compaction-grind Camp. Ex. 3 powder 0.4840.27 42.3 66.8 compaction-grind Comp. Ex. 4 sheet 0.484 0.27 42.0 75.4impact-milling Comp. Ex. 5 sheet 0.484 0.27 42.0 80.1 impact-millingComp. Ex. 6 powder 0.175 0.29 53.6 60.5 impact-milling powder propertiesswollen swollen average specific flowability elastic compressibilityvolume volume ascorbic acid tablet by direct tableting particle surfacebulk repose recovery tablet increase increase disintegration weight sizearea density angle ratio hardness ratio rate hardness time deviation(μm) (m²/g) (g/ml) (°) (%) (kgf) (%) (%/mim) (kgf) (mim) (CV %) Example1 42 1.21 0.42 37 3.8 42 330 190 4.1 2.2 0.6 Example 2 44 1.12 0.44 374.1 45 380 150 4.2 2.4 0.5 Example 3 43 1.05 0.45 38 4.5 41 410 110 4.02.3 0.5 Example 4 51 1.18 0.42 39 4.5 43 502 130 4.5 2.7 0.7 Example 535 1.01 0.48 36 4.2 36 301 270 3.8 1.8 0.5 Comp. Ex. 1 44 0.92 0.44 393.8 35 250 200 3.5 3.8 0.6 Comp. Ex. 2 41 0.90 0.46 39 6.8 32 260 82 3.34.2 0.7 Comp. Ex. 3 40 0.88 0.41 39 8.1 31 180 50 3.2 4.6 0.7 Comp. Ex.4 45 0.75 0.38 45 8.7 25 290 85 2.5 2.4 0.9 Comp. Ex. 5 42 0.45 0.49 399.5 10 500 250 1.8 0.5 0.6 Comp. Ex. 6 65 0.81 0.17 55 13.1 31 310 1803.1 3.0 2.2 *Weight ratio of sodium hydroxide with respect to anhydrouscellulose in alkali cellulose.

As clearly shown in Table 1, in a case where sodium hydroxide in apredetermined weight ratio was contained and compaction-grinding wasused, the specific surface area increased, and the elastic recoveryratio was reduced, and thus the compressibility increased. Accordingly,when a preparation was produced from this powder, a tablet with hightablet hardness was obtained. Furthermore, the swollen volume increaseratio and the swollen volume increase rate increased. Thus, when apreparation was produced from this powder, a preparation with shortdisintegration time was obtained. On the other hand, the results ofComparative Examples 1 to 3 show that in a case wherecompaction-grinding was used but sodium hydroxide in a predeterminedweight ratio was not contained, an obtained powder was poor in specificsurface area, compressibility, swollen volume increase ratio, which isan important swelling property as a disintegrant, tablet hardness, anddisintegration time. Furthermore, in the results of Comparative Examples2 and 3, the swollen volume increase rate, which is an importantswelling property as a disintegrant, was also poor. The results ofComparative Example 6 show that in a case where sodium hydroxide in apredetermined weight ratio was contained but impact milling was usedinstead of compaction-grinding, an obtained powder was poor in specificsurface area, flowability, compressibility, tablet hardness, anddisintegration time, and had large weight variation. In ComparativeExample 4, sheet-shaped pulp was used, and thus alkali cellulosecontaining an excessive amount of sodium hydroxide was used, so that theswollen volume increase rate was poor. Moreover, since an impact-typemill was used, the specific surface area was small, the elastic recoveryratio was large, and the compressibility was low. On the other hand, inComparative Example 5, the amount of fibrous was small due to completedissolution, and thus the repose angle was small, and the flowabilitywas excellent, but the compressibility was low.

1) Orally Disintegrating Tablet

Example 6

Using the low-substituted hydroxypropylcellulose obtained by the methoddescribed in Example 1, an oral rapidly disintegrating tablet wasproduced under the following conditions.

-   -   Tablet composition:        -   erythritol (sieved through 250 μm sieve): 70 parts by weight        -   low-substituted hydroxypropylcellulose: 30 parts by weight        -   magnesium stearate: 0.5 parts by weight    -   Tableting machine: single tableting machine, tableting tester        (manufactured by SANKYO PIO-TECH. CO., Ltd.)    -   Tablet size: diameter 11.3 mm, flat shape    -   Tableting pressure: 10, 25, 50 MPa

The obtained tablet was evaluated, in terms of tablet hardness, orallydisintegration time, and feeling in use. As the orally disintegrationtime, tablets were simply put into the mouths of four healthy adultswithout being chewed in the oral cavities, the time taken for thetablets to be completely dissolved or disintegrated was measured, and anaverage value thereof was calculated. Table 2 shows the results of thetablet hardness and the orally disintegration time.

Comparative Example 7

An oral rapidly disintegrating tablet was produced as in Example 6,except that the low-substituted hydroxypropylcellulose obtained by themethod described in Comparative Example 4 was used. The obtained tabletwas evaluated as in Example 6. Table 2 shows the results.

TABLE 2 tableting tablet hardness oral disintegration time pressure (N)of tablet (sec) (MPa) Example 6 Comp. Ex. 7 Example 6 Comp. Ex. 7 10 3318 18 24 25 42 28 20 29 50 70 60 29 35

Example 6 exhibited higher tablet hardness, and required shorterdisintegration time in the oral cavity, than those in ComparativeExample 7. In Example 6, none of the tablets had a rough surface, andthus creamy feeling in use was provided. On the other hand, ComparativeExample 7 provided bad feeling in use as if paper had been put into themouth.

2) Wet-Agitation Granulation

Example 7

Using the low-substituted hydroxypropylcellulose obtained by the methoddescribed in Example 4, wet agitation granulation was performed, bycharging a powder having the following composition into a verticalgranulator FM-VG-05 (manufactured by POWREX CORPORATION), performingpreliminary mixing for one minute at a main shaft rotational speed of600 rpm and a chopper rotational speed of 1000 rpm, adding 55 g ofwater, and then performing mixing for five minutes.

-   -   Tablet composition:        -   Ethenzamide: 210 g (70 parts by weight)        -   200#lactose: 60 g (20 parts by weight)        -   low-substituted hydroxypropylcellulose: 30 g (10 parts by            weight)

The granulated matter was sieved through a sieve with an opening of 1180μm, and then dried at an air intake temperature of 60° C. and an airflow volume of 70 m³/hr in a fluidized bed drier until the discharge airtemperature was 45° C.

Table 3 shows the average particle size, the bulk density, the tapdensity, the degree of compression, and the repose angle of the obtainedgranule.

It should be noted that the average particle size, the bulk density, andthe repose angle of the obtained granule were measured as in thelow-substituted hydroxypropylcellulose powder, and the tap density andthe degree of compression were measured by the following method.

More specifically, tap density refers to the bulk density in a tightlyfilled state obtained by performing tapping on a vessel in a state inwhich the bulk density can be measured. The tapping refers to anoperation to make a sample be tightly filled, by repeatedly dropping thevessel filled with the sample from a predetermined height therebyproviding the bottom portion with a light impact. Thus, the tap densitycan be measured in the following manner: when weighing has beencompleted after leveling at the upper surface in the measurement of thebulk density, a cap (a component of a powder tester manufactured byHosokawa Micron Corporation) is placed on the vessel, powder is added tothe upper edge of the cap, and tapping is performed 180 times at atapping height of 1.8 cm, and when the tapping has been completed, thecap is removed and weighing is performed after leveling the powder atthe upper surface of the vessel. These operations are performed using apowder tester (PT-D) manufactured by Hosokawa Micron Corporation.

Herein, the degree of compression refers to the degree of volumedecreased, and is calculated from the following equation.Degree of compression (%)=[(tap density−bulk density)/tap density]×100

Next, 0.5 parts by weight of magnesium stearate was added and then mixedwith 100 parts by weight of the granule, and thus a powder for tabletingwas obtained. Using this powder, continuous tableting was performedunder the following conditions.

-   -   Tableting machine: rotary tableting machine (manufactured by        Kikusui Seisakusho Ltd.)    -   Tablet size: diameter 8 mm, radius of curvature 6.5 mm, tablet        weight 200 mg    -   Tableting pressure: main-pressure 1 t, pre-pressure 0.2 t    -   Tableting speed: 40 rpm

The obtained tablet was evaluated, in terms of tablet hardness,disintegration time (test fluid: water) in Disintegration Test accordingto Japanese Pharmacopoeia, tablet friability measured as below followingFriability Test according to Japanese Pharmacopoeia, occurrence ofcapping measured by the number of tablets in which capping occurredafter Friability Test, and tablet weight variation.

In Friability Test, after the test was performed for 16 minutes using afriability test apparatus described in Japanese Pharmacopoeia on 20tablets at 25 rpm, the ratio of weight lost was calculated from thefollowing equation.[{(tablet weight before test)−(tablet weight after test)}/(tablet weightbefore test)]×100

The occurrence of capping was calculated, based on the number of tabletsthat were broken into two layers, after Friability Test above.

The tablet weight deviation was obtained by measuring the weight of 20tablets and calculating their coefficient of variation (CV value).

Table 4 shows the obtained results.

Comparative Example 8

Wet agitation granulation was performed as in Example 7, except that thelow-substituted hydroxypropylcellulose obtained by the method describedin Comparative Example 4 was used. Table 3 shows the average particlesize, the bulk density, the tap density, the degree of compression, andthe repose angle of the obtained granule.

Next, continuous tableting was performed as in Example 7, and theresultant was evaluated. Table 4 shows the results.

Comparative Example 9

Wet agitation granulation was performed as in Example 7, except thatmicrocrystalline cellulose Ceolus PH-101 (manufactured by Asahi KaseiChemicals) was used instead of the low-substitutedhydroxypropylcellulose. Herein, since microcrystalline cellulose haswater retentivity lower than that of low-substitutedhydroxypropylcellulose, water was reduce to 36 g. Table 3 shows theaverage particle size, the bulk density, the tap density, the degree ofcompression, and the repose angle of the obtained granule.

Next, continuous tableting was performed as in Example 7, and theresultant was evaluated. Table 4 shows the results.

TABLE 3 average particle bulk tap degree of repose size density densitycompression angle (μm) (g/ml) (g/ml) (%) (°) Example 7 96.1 0.512 0.67624.3 36 Comp. Ex. 8 96.7 0.479 0.703 31.9 41 Comp. Ex. 9 95.3 0.4940.679 27.2 39

In Example 7, the bulk density was higher and the weight was heavier,and the degree of compression and the repose angle were smaller thanthose of Comparative Examples 8 and 9, and thus a granule with excellentflowability was obtained.

TABLE 4 disintegration weight tablet tablet time of loss of occurrenceweight hardness tablet talbet of capping deviation (N) (min) (%) (%) (CV%) Example 7 94 2.1 0.53 0 0.52 Comp. 53 0.9 0.63 0 1.1 Ex. 8 Comp. 449.2 2.5 40 0.76 Ex. 9

In Example 7, an excellent preparation was obtained in which the tablethardness was higher and the tablet weight variation was lower than thoseof Comparative Example 8. In Comparative Example 9 in whichmicrocrystalline cellulose was used, capping occurred, the tabletfriability was high, and the tablet hardness was low, but a preparationin Example 7 was excellent in all of the evaluation items.

3) Fluidized Bed Granulation

Example 8

Using the low-substituted hydroxypropylcellulose obtained by the methoddescribed in Example 1, granulation was performed, by charging a powderhaving the following composition into a fluidized bed granulating deviceMultiplex MP-01 (manufactured by POWREX CORPORATION), and spraying 60 gof an aqueous 5% by weight solution of hydroxypropylmethylcelluloseTC-5R (manufactured by Shin-Etsu Chemical Co., Ltd.) at a rate of 10g/min, at an air intake temperature 60° C., an air flow volume of 50m³/hr, and a discharge air temperature of 30 to 35° C.

-   -   Tablet composition:        -   Acetaminophen: 80 g (40 parts by weight)        -   200#lactose: 28 g (14 parts by weight)        -   Cornstarch: 12 g (6 parts by weight)        -   low-substituted hydroxypropylcellulose: 80 g (40 parts by            weight)

Table 5 shows the average particle size, the bulk density, the tapdensity, the degree of compression, and the repose angle of the obtainedgranule.

Next, 0.5 parts by weight of magnesium stearate was added and then mixedwith 100 parts by weight of the granule, and thus a powder for tabletingwas obtained. Using this powder, continuous tableting was performed asin Example 7. The obtained tablet was evaluated, in terms of tablethardness, disintegration time (test fluid: water) in Disintegration Testaccording to Japanese Pharmacopoeia, and tablet weight variation. Table6 shows the results.

Comparative Example 10

Fluidized bed granulation was performed as in Example 8, except that thelow-substituted hydroxypropylcellulose obtained by the method describedin Comparative Example 4 was used. Table 5 shows the average particlesize, the bulk density, the tap density, the degree of compression, andthe repose angle of the obtained granule.

Next, continuous tableting was performed as in Example 8, and theresultant was evaluated. Table 6 shows the results.

Comparative Example 11

Fluidized bed granulation was performed as in Example 8, except that thelow-substituted hydroxypropylcellulose obtained by the method describedin Comparative Example 5 was used. Table 5 shows the average particlesize, the bulk density, the tap density, the degree of compression, andthe repose angle of the obtained granule.

Next, continuous tableting was performed as in Example 8, and theresultant was evaluated. Table 6 shows the results.

TABLE 5 average particle bulk tap degree of repose size density densitycompression angle (μm) (g/ml) (g/ml) (%) (°) Example 8 150 0.249 0.34427.6 39 Comp. Ex. 10 155 0.159 0.246 35.4 48 Comp. Ex. 11 162 0.1880.270 30.4 42

In Example 8, the bulk density was higher and the weight was heavier,and the degree of compression and the repose angle were smaller thanthose of Comparative Examples 10 and 11, and thus a granule withexcellent flowability was obtained.

TABLE 6 disintegration tablet tablet time of weight hardness tabletdeviation (N) (min) (CV %) Example 8 101 1.0 0.52 Comp. Ex. 10 69 0.71.1 Comp. Ex. 11 37 0.5 0.6

In Example 8, an excellent preparation was obtained in which the tablethardness was higher and the tablet weight variation was smaller thanthose of Comparative Examples 10 and 11.

4) Extrusion Granulation

Example 9

Using the low-substituted hydroxypropylcellulose obtained by the methoddescribed in Example 4, wet agitation granulation was performed, bycharging a powder having the following composition into a verticalgranulator FM-VG-05 (manufactured by POWREX CORPORATION), performingpreliminary mixing for one minute at a main shaft rotational speed of600 rpm and a chopper rotational speed of 1000 rpm, adding 50 g ofwater, and then performing mixing for five minutes.

-   -   Tablet composition:        -   Aspirin: 279 g (93 parts by weight)        -   low-substituted hydroxypropylcellulose: 15 g (5 parts by            weight)        -   hydroxypropylmethylcellulose TC-5E: 6 g (2 parts by weight)

Next, extrusion granulation of the wet powder was performed using anextrusion granulator Dome Gran (manufactured by DALTON CORPORATION) witha 1.0 mmΦscreen. Table 7 shows the granulating speed expressed in termsof a solid content. Furthermore, the obtained extrusion-granulatedmatter was spheroidized using a marumerizer (manufactured by DALTONCORPORATION) at 750 rpm. Then, the resultant was dried at an air intaketemperature of 60° C. and an air flow volume of 70 m³/hr in a fluidizedbed drier until the discharge air temperature was 45° C. The obtainedgranule was evaluated in terms of granule strength, and disintegrationtime (test fluid: water) in Disintegration Test according to JapanesePharmacopoeia. Table 7 shows the results.

The granule strength was calculated from the following equation as theratio of weight lost, after charging 10 g of the granules and 20 glassbeads having a diameter of 5 mm into a friability test apparatusdescribed in Japanese Pharmacopoeia, and performing the test for 4minutes at 25 rpm.[{(granule weight before test)−(granule weight after test)}/(granuleweight before test)]×100

Comparative Example 12

Extrusion granulation was performed as in Example 9, except that thelow-substituted hydroxypropylcellulose obtained by the method describedin Comparative Example 4 was used. Table 7 shows the granulating speedexpressed in terms of a solid content. The obtained wet-granulatedmatter was spheroidized and dried as in Example 9.

The obtained granule was evaluated in terms of granule strength, anddisintegration time (test fluid: water) in Disintegration Test accordingto Japanese Pharmacopoeia. Table 7 shows the results.

TABLE 7 disintegration granulating speed granule strength time ofgranule (g/min) (%) (min) Example 9 274.6 0.7 0.8 Comp. Ex. 12 108.6 2.10.6

In Example 9, an excellent preparation was obtained in which thegranulating speed was faster, the productivity was higher, and thegranule strength of the obtained granule was higher than those ofComparative Example: 12.

5) Dry Granulation

Example 10

Using the low-substituted hydroxypropylcellulose obtained by the methoddescribed in Example 4, dry granulation was performed on a powder havingthe following composition, with a roller compactor MINI (manufactured byFREUND), at a roll pressure of 4 MPa, a roll rotational speed of 5 rpm,and a screw rotational speed of 12 rpm.

-   -   Tablet composition:        -   ascorbic acid: 50 g (10 parts by weight)        -   200#lactose: 245 g (49 parts by weight)        -   Cornstarch: 105 g (21 parts by weight)        -   low-substituted hydroxypropylcellulose: 100 g (20 parts by            weight)        -   magnesium stearate: 2.5 g (0.5 parts by weight)

The granulated matter was sieved through a sieve with an opening of 250μm, and continuous tableting was performed with granulated matter underthe following conditions.

-   -   Tableting machine: rotary tableting machine (manufactured by        Kikusui Seisakusho Ltd.)    -   Tablet size: diameter 8 mm, radius of curvature 6.5 mm    -   Tablet weight: 200 mg    -   Tableting pressure: main-pressure 1 t, pre-pressure 0.2 t    -   Tableting speed: 40 rpm

The obtained tablet was evaluated, in terms of tablet hardness, anddisintegration time (test fluid: water) in Disintegration Test accordingto Japanese Pharmacopoeia. Table 8 shows the results.

Comparative Example 13

Dry granulation was performed as in Example 10, except that thelow-substituted hydroxypropylcellulose obtained by the method describedin Comparative Example 4 was used. Continuous tableting was performed asin Example 10. The obtained tablet was evaluated, in terms of tablethardness, and disintegration time (test fluid: water) in DisintegrationTest according to Japanese Pharmacopoeia. Table 8 shows the results.

TABLE 8 tablet hardness tablet disintegration time (N) (min) Example 1060 1.1 Comp. Ex. 13 41 0.8

In Example 10, a preparation was obtained in which the disintegrationtime was similar to that of Comparative Example 13, but the tablethardness was higher than that of Comparative Example 13.

The invention claimed is:
 1. A method for producing a low-substitutedhydroxypropylcellulose powder having a molar substitution number peranhydrous glucose unit of 0.05 to 1.0, which is insoluble in water andswollenable by absorbing water, consisting essentially of the steps of:(1) adding an aqueous sodium hydroxide solution to powdered pulp in sucha manner that weight ratio of sodium hydroxide with respect to anhydrouscellulose is 0.1 to 0.3 so as to obtain alkali cellulose; (2)etherifying the obtained alkali cellulose so as to obtain a crudereaction product; (3) neutralizing the sodium hydroxide contained in theobtained crude reaction product without performing a step of dissolvingpart or whole of the crude reaction product; (4) washing and dehydratingthe resultant; (5) drying; and (6) pulverizing by compaction-grinding.2. The method for producing a low-substituted hydroxypropylcellulosepowder according to claim 1, wherein in said step of washing anddehydrating, said resultant is washed and dehydrated such that a watercontent is not greater than 65% by weight.